---
_id: '12251'
abstract:
- lang: eng
  text: Amyloid formation is linked to devastating neurodegenerative diseases, motivating
    detailed studies of the mechanisms of amyloid formation. For Aβ, the peptide associated
    with Alzheimer’s disease, the mechanism and rate of aggregation have been established
    for a range of variants and conditions <jats:italic>in vitro</jats:italic> and
    in bodily fluids. A key outstanding question is how the relative stabilities of
    monomers, fibrils and intermediates affect each step in the fibril formation process.
    By monitoring the kinetics of aggregation of Aβ42, in the presence of urea or
    guanidinium hydrochloride (GuHCl), we here determine the rates of the underlying
    microscopic steps and establish the importance of changes in relative stability
    induced by the presence of denaturant for each individual step. Denaturants shift
    the equilibrium towards the unfolded state of each species. We find that a non-ionic
    denaturant, urea, reduces the overall aggregation rate, and that the effect on
    nucleation is stronger than the effect on elongation. Urea reduces the rate of
    secondary nucleation by decreasing the coverage of fibril surfaces and the rate
    of nucleus formation. It also reduces the rate of primary nucleation, increasing
    its reaction order. The ionic denaturant, GuHCl, accelerates the aggregation at
    low denaturant concentrations and decelerates the aggregation at high denaturant
    concentrations. Below approximately 0.25 M GuHCl, the screening of repulsive electrostatic
    interactions between peptides by the charged denaturant dominates, leading to
    an increased aggregation rate. At higher GuHCl concentrations, the electrostatic
    repulsion is completely screened, and the denaturing effect dominates. The results
    illustrate how the differential effects of denaturants on stability of monomer,
    oligomer and fibril translate to differential effects on microscopic steps, with
    the rate of nucleation being most strongly reduced.
acknowledgement: This work was supported by grants from the Swedish Research Council
  (grant no. 2015-00143) and the European Research Council (grant no. 340890).
article_number: '943355'
article_processing_charge: No
article_type: original
author:
- first_name: Tanja
  full_name: Weiffert, Tanja
  last_name: Weiffert
- first_name: Georg
  full_name: Meisl, Georg
  last_name: Meisl
- first_name: Samo
  full_name: Curk, Samo
  last_name: Curk
- first_name: Risto
  full_name: Cukalevski, Risto
  last_name: Cukalevski
- first_name: Anđela
  full_name: Šarić, Anđela
  id: bf63d406-f056-11eb-b41d-f263a6566d8b
  last_name: Šarić
  orcid: 0000-0002-7854-2139
- first_name: Tuomas P. J.
  full_name: Knowles, Tuomas P. J.
  last_name: Knowles
- first_name: Sara
  full_name: Linse, Sara
  last_name: Linse
citation:
  ama: Weiffert T, Meisl G, Curk S, et al. Influence of denaturants on amyloid β42
    aggregation kinetics. <i>Frontiers in Neuroscience</i>. 2022;16. doi:<a href="https://doi.org/10.3389/fnins.2022.943355">10.3389/fnins.2022.943355</a>
  apa: Weiffert, T., Meisl, G., Curk, S., Cukalevski, R., Šarić, A., Knowles, T. P.
    J., &#38; Linse, S. (2022). Influence of denaturants on amyloid β42 aggregation
    kinetics. <i>Frontiers in Neuroscience</i>. Frontiers Media. <a href="https://doi.org/10.3389/fnins.2022.943355">https://doi.org/10.3389/fnins.2022.943355</a>
  chicago: Weiffert, Tanja, Georg Meisl, Samo Curk, Risto Cukalevski, Anđela Šarić,
    Tuomas P. J. Knowles, and Sara Linse. “Influence of Denaturants on Amyloid Β42
    Aggregation Kinetics.” <i>Frontiers in Neuroscience</i>. Frontiers Media, 2022.
    <a href="https://doi.org/10.3389/fnins.2022.943355">https://doi.org/10.3389/fnins.2022.943355</a>.
  ieee: T. Weiffert <i>et al.</i>, “Influence of denaturants on amyloid β42 aggregation
    kinetics,” <i>Frontiers in Neuroscience</i>, vol. 16. Frontiers Media, 2022.
  ista: Weiffert T, Meisl G, Curk S, Cukalevski R, Šarić A, Knowles TPJ, Linse S.
    2022. Influence of denaturants on amyloid β42 aggregation kinetics. Frontiers
    in Neuroscience. 16, 943355.
  mla: Weiffert, Tanja, et al. “Influence of Denaturants on Amyloid Β42 Aggregation
    Kinetics.” <i>Frontiers in Neuroscience</i>, vol. 16, 943355, Frontiers Media,
    2022, doi:<a href="https://doi.org/10.3389/fnins.2022.943355">10.3389/fnins.2022.943355</a>.
  short: T. Weiffert, G. Meisl, S. Curk, R. Cukalevski, A. Šarić, T.P.J. Knowles,
    S. Linse, Frontiers in Neuroscience 16 (2022).
date_created: 2023-01-16T09:56:43Z
date_published: 2022-09-20T00:00:00Z
date_updated: 2023-08-04T09:48:56Z
day: '20'
ddc:
- '570'
department:
- _id: AnSa
doi: 10.3389/fnins.2022.943355
external_id:
  isi:
  - '000866287100001'
file:
- access_level: open_access
  checksum: e67d16113ffb4fb4fa38a183d169f210
  content_type: application/pdf
  creator: dernst
  date_created: 2023-01-30T09:15:13Z
  date_updated: 2023-01-30T09:15:13Z
  file_id: '12442'
  file_name: 2022_FrontiersNeuroscience_Weiffert2.pdf
  file_size: 19798610
  relation: main_file
  success: 1
file_date_updated: 2023-01-30T09:15:13Z
has_accepted_license: '1'
intvolume: '        16'
isi: 1
keyword:
- General Neuroscience
language:
- iso: eng
month: '09'
oa: 1
oa_version: Published Version
publication: Frontiers in Neuroscience
publication_identifier:
  issn:
  - 1662-453X
publication_status: published
publisher: Frontiers Media
quality_controlled: '1'
scopus_import: '1'
status: public
title: Influence of denaturants on amyloid β42 aggregation kinetics
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 16
year: '2022'
...